Walter Flato Goodman Center for Comparative Medical Genetics

Medical genetics is the broad field of science that deals with the role of genes in disease. This involves the identification and characterization of genes that cause disease, as well as the application of genetic knowledge to the diagnosis, treatment, and prevention of genetic diseases. Genetic diseases include disorders in which a single gene mutation is both necessary and sufficient to cause the disease, as well as complex disorders involving the interactions of multiple genes and other factors.

Essentially all of the genetic diseases that occur in humans can be expected to occur in other mammals due to the basic homology between the human genome and the genomes of other mammalian species. However, the recognition of genetic disorders in animals depends upon the degree of medical surveillance utilized and the amount of family information that is available. Domestic animals, particularly the dog and cat, are a rich source of potential models because they are examined by veterinarians for individual diseases at a level that is comparable to human medicine.

The Walter Flato Goodman Center for Comparative Medical Genetics (CCMG) is designed to foster interdisciplinary research and research training in this field through the development of shared resources. The investigators focus their research primarily on naturally-occurring genetic diseases of animals that are true homologs of human genetic diseases.

The CCMG dates from 1974 when an Animal Models Core was funded through the NIH Human Genetics Center grant. In 1985 a grant was awarded by the NIH National Center for Research Resources (NCRR) to establish the National Referral Center for Animal Models of Human Genetic Disease, which is the main mechanism through which new genetic diseases are identified and characterized. The multi-departmental Section of Medical Genetics was the forerunner and model for the center concept developed in the School of Veterinary Medicine in the 1990’s. The program was formally designated as the Center for Comparative Medical Genetics in 1994. Dr. Donald Patterson was the founder and director of this program for 25 years until his retirement in 1998, when Dr. Wolfe was appointed to succeed him. In 2003 Mr. Walter Flato Goodman committed an endowment for future support of the center and it was named in his honor. Mr. Goodman was a long-time dog breeder, judge, and member of the American Kennel Club. He was also a member of the Board of Overseers of the School of Veterinary Medicine.

Investigators at Penn's Veterinary School have been at the forefront of comparative medical genetics research for over three decades. The contributions fall into two broad categories in terms of application of the knowledge gained:

Contributions to the diagnosis and control of genetic diseases within animal populations, particularly the dog and cat

Contributions to the understanding and treatment of human disease using the animal homologs as models for research in areas such as gene therapy

This includes the discovery of more than 50 new animal homologs of human genetic diseases in various species. Many of the findings have been published in leading scientific journals. Scientists in the CCMG have been highly successful in attracting grant funding from federal and private sources. Since genetics is basic to all disciplines in the medical specialties and the basic biological sciences, the CCMG investigators interact with faculty and programs throughout the Veterinary School and the University.

The investigators in the CCMG interdisciplinary are drawn from several departments of the School of Veterinary Medicine and the School of Medicine. The investigators also have numerous collaborations within the University and at other universities, research institutes, biotechnology companies, NIH, and internationally. The CCMG members have key roles in University-wide programs including graduate groups in Cell and Molecular Biology, Biochemistry and Molecular Biophysics, Immunology, and Neuroscience; The David Mahoney Institute of Neurological Sciences; The Mental Retardation Research Center; Abramson Family Cancer Research Institute; and the Penn Genomics Institute. The programs within the CCMG fall into three general categories.

Studies in Established Animal Models of Human Genetic Disease

These studies are aimed primarily at the investigation of new approaches to understanding and treating the corresponding disease in human patients. Current studies include comparative mapping of disease genes in the dog, studies of the pathogenesis of genetic diseases in dogs and cats, and gene therapy studies in mice, cats, and dogs. This work contributes basic knowledge needed in both veterinary and human medicine to define the molecular nature of genetic diseases, and to understand the intermediate steps between the disease gene and the clinical and pathologic phenotype in affected individuals. These are primarily conducted through individual research grants, mostly from NIH. Many of these grants involve collaborations among the CCMG laboratories.

Clinical Genetics Research

This research concentrates on the identification of naturally occurring genetic diseases of animals and characterization of these diseases at the clinical, pathologic, and molecular genetic levels. One objective is to provide the basic knowledge needed to provide useful animal models of disease for further investigation. Potential new genetic diseases are diagnosed and initially characterized under an NCRR Center Grant. The second objective is to use the research information to accurately diagnose and reduce the frequency of genetic disorders within the animal populations in which they occur. This is done in the Josephine Deubler Genetic Testing Laboratory, utilizing a variety of DNA and other tests, as a service to the veterinary, and dog and cat breeding communities. A comprehensive computerized knowledge base on genetic diseases of the dog, The Canine Genetic Disease Information System, is a computerized database that has been developed by Dr. D.F. Patterson and is expected to assist veterinarians, geneticists, and dog breeders in eliminating disease-producing genes from breed populations.

The frontiers of medical genetics and molecular medicine are only limited by the lack of understanding of many fundamental disease processes and the ability to manipulate biological processes by recombinant DNA technologies. The benefits will be applicable directly to domestic animal diseases and the focused investigation of carefully chosen animal diseases will provide key information. The major directions for future research will be in the following areas:

Comparative Genomics

Finding and Characterizing Disease Genes in Animals

The development of methods to map mammalian genomes has revolutionized the approach to identification, isolation and characterization of the mutations that underlie genetic diseases. Recent advances in genome sciences methods have made it more practical to use this approach in the dog and cat. The detection and study of a large variety of disorders with recessive and complex patterns of inheritance is greatly facilitated in the dog and cat because there is enough periodic inbreeding to reveal these defects, but the alleles that confer susceptibility still exist in sufficient frequencies in these populations to be available for study. Breeds of dogs and cats have the same advantages for such studies as human genetic isolates, but the number and diversity of the isolates (breeds) are many times greater than is found in the world’s human population. This is a resource in comparative medical genetics that is waiting to be mined for the purpose of better understanding of human disease, as well as for the improvement of animal health. This effort in the CCMG is focused on avenues of research where the animal models offer unique ways to investigate the genetics and biology. The diseases to be studied are selected for the medical characteristics, the underlying pathology, where the inheritance is sufficiently well documented that a focused investigation can be performed, and where scientific progress can be accelerated by studying the animal disease. To learn more, visit the Penn Genome Frontiers Institute.

Mechanisms of Disease

Understanding the Cellular and Molecular Basis of Pathology

Although new disease-causing genes are being identified at a rapid rate, there are great gaps in knowledge of how the mutant genes cause the observed clinical and histopathological abnormalities. Animals with specific genetic diseases constitute a major resource for studying the natural history of rare disorders. Because cohorts of sufficient sizes can be studied, various stages of disease progression can be evaluated. Many studies on animal models have been instrumental in improving understanding of the human disease, where it is often impossible to obtain affected tissues during the course of the disease. In addition, a thorough understanding of the molecular and cellular abnormalities of each disease is critical for the rational design of new therapies.

Gene Therapy

Using Gene Based Approaches to Treatment

Advances in molecular biology are being developed into entirely new methods of treating disease. The concept of gene therapy for single gene inherited disorders is compellingly simple: treat a disease at the fundamental level of the DNA defect by inserting a normal copy of the gene into the affected cells of a patient to correct the biochemical deficiency responsible for the symptoms. However, after more than15 years of investigation by many laboratories, this goal remains elusive. It has been particularly difficult to scale up the methods from rodents to large mammals, including humans. The animal models being studied by CCMG investigators provide experimental platforms for understanding the problems of delivering genes successfully to a large mammal under actual disease conditions. In veterinary clinical medicine the best treatment for these very rare disorders will be to remove the mutant allele from the breeding stock. However, there are a number of diseases of veterinary importance where gene transfer methods may be applicable, e.g. cancers, degenerative joint disease in horses, neurologic abnormalities, and common metabolic diseases such as diabetes. Effective application in a clinical setting will depend on having a thorough understanding of the underlying biochemical, cellular, and pathologic mechanisms of each disease.

Biological Imaging

Direct viewing of Life Processes, Pathology and Treatment

Biological imaging using noninvasive methods is changing the landscape not only of clinical medicine but of research into biological processes in their natural settings. CCMG investigators use techniques such as NMR to study the progression of disease and responses to treatments and to gain new insight into pathologic mechanisms. Future research in this area will be done in close collaboration with the Metabolic Magnetic Resonance Research and Computing Center and the Department of Radiology in the School of Medicine to take advantage of the infrastructure, expertise, and instrumentation that is available to the biomedical community at Penn.

The Walter Flato Goodman Center for Comparative Medical Genetics is defined by its renown faculty and their research:

Inherited retinal degeneration disease: This laboratory studies the inheritance of retinal degeneration in dogs as a model for human diseases. These include efforts to identify the genes and locate the mutations associated with several separately inherited forms of progressive retinal atrophy (PRA), a significant disease of dogs that is also the genetic analog of retinitis pigmentosa, a group of retinal degenerations inherited in human families. This laboratory is involved in the construction of the dog genome map and is also using genomics analysis to map behavioral traits in canids.

Inherited retinal degeneration: Inherited retinal degenerations constitute a major cause of blindness in dogs and humans worldwide, and share a common feature: the degeneration and death of the photoreceptor cells. Although a significant number of genes associated with retinitis pigmentosa (RP) have been identified, there is currently no treatment available. Dr. Beltran's research is focused at examining the cellular and molecular mechanisms of photoreceptor death in canine models of retinal degeneration, and developing novel therapeutic approaches aimed at curing or slowing the progression of this group of diseases in dogs and human patients.

Inherited skin diseases: Dr. Casal is investigating inherited skin diseases. X-linked hypohidrotic ectodermal dysplasia (HED) is the most common developmental disorder affecting the skin and its appendages in humans. This laboratory is studying the genetic, molecular, developmental basis of canine HED. Several other canine models of human genodermatoses (junctional epidermolysis bullosa, ichthyosis, black hair follicular dysplasia, and lupoid dermatosis) have also been identified in the dog, which are at various stages of characterization. These diseases provide an unparalleled group of models for investigation.

Inherited defects of the immune system: This laboratory studied the inherited defects of the immune system. Clinical research in the WFG-CCMG led to the discovery of a form of severe congenital immune deficiency with x-linked recessive inheritance in the dog. The dog disease involves the same gene as that involved in human X-SCID, the most common form of inherited immune deficiency in children. The model is being used to study basic questions of immune system development, as well as potential treatments s bone marrow transplantation and gene therapy.

Metabolic and blood diseases: This laboratory studies inherited metabolis and blood diseases. The research focuses on the clinical, pathological, and genetic characterization of the disorders, as well as their treatment, including transfusion support strategies. A major focus is the search for new models of hereditary disorders in dogs and cats, which represent homologues of human genetic diseases, including enzyme deficiencies, and blood cell and hemostatic defects. Significant effort is directed toward understanding the biochemical basis of genetic diseases and variants of mutations.

Lysosomal storage diseases: This laboratory focuses on lysosomal storage diseases. The WFG-CCMG has identified animal models of several of these disorders, each involving a separate enzymatic defect. The animals are accurate models of the human diseases and have provided significant new insights into the natural history and mechanisms of pathogenesis. The primary interest of this laboratory is in the pathology and treatment of bones, joints and visceral organs. The animal models have been used extensively for experiments in bone marrow transplantation, enzyme replacement, and gene therapy.

Identification of disease causing genes: This laboratory is involved in characterizing mutations in disease causing genes in a number of large animal models, currently focused on identifying genes involved in complex patterns of inheritance. The main model is congenital heart malformations in the dog, which constitutes one of the largest classes of human birth defects. The pioneering studies of D.F. Patterson showed that the most common forms are essentially the same in humans and dogs, and are genetically determined. Studies are directed toward gene mapping, identification of specific genes in the canine model, and correlating the specific understanding of the developmental events.

Gene therapy for cardiology: research initially focused on the identification and characterization of juvenile dilated cardiomyopathy in Portuguese water dogs and has led to several ongoing studies, including most recently the evaluation of various candidate genes for use in a therapeutic gene transfer approach to improve cardiac function in failing hearts. Ultimately the goal is to translate this work to gene transfer treatment approaches for canine idiopathic dilated cardiomyopathy and human heart failure. Studies are also underway evaluating therapeutic gene transfer approaches to treat cardiac and skeletal muscle dysfunction in X-linked muscular dystrophy golden retriever dogs.

Imaging and pathology of neurogenetic disease: This investigator is interested in non-invasive imaging of neurological diseases using magnetic resonance imaging (MRI) methods. The laboratory has developed MR methods for quantitative measurements of dysmyelination in the Niemann-Pick C and the alpha-mannosidosis cat. Current research is directed to developing more sensitive methods to analyze pathology in the CNS, such as diffusion weighted imaging and spectroscopy. The long-term goal is to develop strategies to understand neurological diseases in situ, as well as to follow the natural progression of the diseases and responses to experimental therapies.

Gene therapy for the central nervous system: This laboratory investigates direct gene transfer and neural stem cell engraftment in the CNS. Various vector systems and routes of delivery are being tested using animal disease models as a platform to evaluate therapeutic effectiveness. Most of the work has centered on the lysosomal storage diseases that, like most inherited metabolic disorders in the CNS, have global lesions. Advances in treatment of the mouse CNS are being extended to the dog and cat models to study the significant scale-up barriers that must be overcome to effectively treat the human brain. This lab is also pursuing studies on reporter genes for non-invasive imaging by PET and MRI in the brain.